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UniProt release 2016_10

Published November 2, 2016

Headline

N-acyl amino acids: a new treatment for obesity?

Mitochondria play a fundamental role in energy production. After glycolysis, glucose products are imported into the mitochondrial matrix, where they go through the citric acid cycle. The electrons produced in this process are transported from one protein complex to the next in the mitochondrial inner membrane. The final electron acceptor is molecular oxygen, which is ultimately reduced to water. During electron transport, the participating protein complexes pump protons out of the matrix space into the intermembrane space and thus create a concentration gradient. This gradient is used by ATP synthase to power the phosphorylation of ADP into ATP. However not all energy liberated from the oxidation of dietary substrates is converted into ATP. Protons can leak back to the matrix through the inner membrane independently of ATP synthase and the energy accumulated is dissipated as heat. Several proteins are known to be involved in this process, called “uncoupled respiration”. One of them, UCP1 has been most extensively studied in the context of thermogenesis mediated by brown and beige adipose tissues.

Adaptive thermogenesis does not rely exclusively upon UCP1. Adipose tissues secrete many bioactive proteins, some of which potentially play a role in the regulation of energy expenditure. Recently, Long et al. identified a protein secreted by brown and beige fat cells, PM20D1. This protein is co-expressed with UCP1 in adipocytes. When injected with PM20D1 viral expression vectors and placed on high fat diet for a period of 47 to 54 days, mice exhibited a blunted weight gain, due to a massive reduction in fat mass compared with control animals. There was no difference in food intake, nor in movement between treated and untreated animals, suggesting the activation of a thermogenic gene program in the classical brown fat (BAT), subcutaneous inguinal white fat (iWAT), or both. Interestingly, UCP1 levels were unchanged in these experiments.

In vitro, PM20D1 appeared to be a bidirectional N-acyl amino acid synthase and hydrolase, the synthase activity being lower than the hydrolase activity. In vivo, plasma levels of N-oleyl-phenylalanine (C18:1-Phe) were indeed elevated in mice injected with PM20D1 expression vector. But what is the effect of N-lipidated amino acids on cells? When treated with N-acyl amino acids, primary BAT adipocytes and differentiated iWAT cells showed increased oxygen consumption in a UCP1-independent manner, indicating respiratory uncoupling activity of these compounds. The N-acyl amino acids tested (N-arachidonyl-glycine (C20:4-Gly), C20:4-Phe, and C18:1-Phe) acted directly on mitochondria, possibly by interaction with mitochondrial transporter proteins, such as SLC25A4 and SLC25A5. Of note, SLC25A4 and SLC25A5 exhibit ADP/ATP symport activity, but are also thought to translocate protons across the inner membrane. Finally treatment of obese mice with C18:1-Leu induced weight loss through the reduction of fat mass and improved glucose tolerance tests.

In the 1930s, the mitochondrial uncoupling 2,4 dinitrophenol (DNP) was used in diet pills to stimulate metabolism and promote weight loss and actually it can still be purchased on the internet for this purpose. Though quite efficient in terms of weight loss, this drug has severe side effects. It can cause an excessive rise in body temperature due to the heat produced during uncoupling. DNP overdose causes fatal hyperthermia, with body temperature rising to as high as 44oC shortly before death. Will N-acyl-amino acids become a new, this time innocuous, treatment of choice for obesity? It’s difficult to anticipate. Chronic treatment of mice with C18:1-Phe or C20:4-Gly not only increases energy expenditure, with no effects on movement, but also reduces food intake, which obviously also contributes to weight loss. However, several N-acyl-amino acids have other biological functions, besides respiratory uncoupling, and hence may have other (undesirable?) effects. Nevertheless the study of Long et al. sheds light on new endogenous mitochondrial uncouplers and new thermogenic mechanisms that are undoubtedly worth further investigation.

As of this release, PM20D1 entries have been updated and are publicly available.

UniProtKB news

Cross-references to DisGeNET

Cross-references have been added to DisGeNET, a discovery platform for the dynamical exploration of human diseases and their genes.

Cross-references to OpenTargets

Cross-references have been added to OpenTargets. This Target Validation platform brings together information on the relationships between potential drug targets and diseases. The core concept is to identify evidence of an association between a target and disease from various data types.

Change of the cross-references to PhosphoSite

The PhosphoSite resource has changed its name to PhosphoSitePlus and we have updated our cross-references to reflect this name change.

Change of the cross-references to SMR

We have modified our cross-references to the SWISS-MODEL Repository (SMR) database. These cross-references used to indicate the sequence ranges of the UniProt canonical sequence that can be modelled with high confidence. This information is now no longer available in our cross-references, but you can get the most up-to-date data in SMR which is now updated weekly for several model organisms, or by triggering yourself the update of a specific entry in SMR.

Change of RDF representation of the cross-references to PDB

We have modified the representation of our cross-references to PDB. These cross-references indicate the sequence ranges of the UniProt canonical sequence that are covered by a PDB structure when this data is available. This piece of information was provided via a reification of the cross-reference statement and each range was represented with a chain property that had a string literal value. We have introduced a new chainSequenceMapping property to simplify this description.

New term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

Hydroxylated arginine

N6-(beta-hydroxybutyrate)lysine

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